Cardiac-derived CTRP9 protects against myocardial ischemia/reperfusion injury via calreticulin-dependent inhibition of apoptosis.

Abstract

Cardiokines play an essential role in maintaining normal cardiac functions and responding to acute myocardial injury. Studies have demonstrated the heart itself is a significant source of C1q/TNF-related protein 9 (CTRP9). However, the biological role of cardiac-derived CTRP9 remains unclear. We hypothesize cardiac-derived CTRP9 responds to acute myocardial ischemia/reperfusion (MI/R) injury as a cardiokine. We explored the role of cardiac-derived CTRP9 in MI/R injury via genetic manipulation and a CTRP9-knockout (CTRP9-KO) animal model. Inhibition of cardiac CTRP9 exacerbated, whereas its overexpression ameliorated, left ventricular dysfunction and myocardial apoptosis. Endothelial CTRP9 expression was unchanged while cardiomyocyte CTRP9 levels decreased after simulated ischemia/`reperfusion (SI/R) in vitro. Cardiomyocyte CTRP9 overexpression inhibited SI/R-induced apoptosis, an effect abrogated by CTRP9 antibody. Mechanistically, cardiac-derived CTRP9 activated anti-apoptotic signaling pathways and inhibited endoplasmic reticulum (ER) stress-related apoptosis in MI/R injury. Notably, CTRP9 interacted with the ER molecular chaperone calreticulin (CRT) located on the cell surface and in the cytoplasm of cardiomyocytes. The CTRP9-CRT interaction activated the protein kinase A-cAMP response element binding protein (PKA-CREB) signaling pathway, blocked by functional neutralization of the autocrine CTRP9. Inhibition of either CRT or PKA blunted cardiac-derived CTRP9's anti-apoptotic actions against MI/R injury. We further confirmed these findings in CTRP9-KO rats. Together, these results demonstrate that autocrine CTRP9 of cardiomyocyte origin protects against MI/R injury via CRT association, activation of the PKA-CREB pathway, ultimately inhibiting cardiomyocyte apoptosis.

• Authors: Dajun Zhao, Pan Feng, Yang Sun, Zhigang Qin, Zhengbin Zhang, Yanzhen Tan, Erhe Gao, Wayne Bond Lau, Xinliang Ma, Jian Yang, Shiqiang Yu, Xuezeng Xu, Dinghua Yi, Wei Yi
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 7 Pg. 723 (06 20 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 29925877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adiponectin
• CTRP9 protein, mouse
• Calreticulin
• Cardiotonic Agents
• Cyclic AMP Response Element-Binding Protein
• Glycoproteins
• Cyclic AMP-Dependent Protein Kinases

Topics

• Adiponectin (deficiency, metabolism)
• Animals
• Apoptosis
• Autocrine Communication
• Calreticulin (metabolism)
• Cardiotonic Agents (metabolism)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Glycoproteins (deficiency, metabolism)
• Heart Ventricles (pathology, physiopathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Myocardial Reperfusion Injury (pathology, physiopathology, prevention & control)
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• Phenotype
• Rats, Sprague-Dawley